Targeting the Ip6k2-Runx2 axis disrupts osteoblast-osteoclast coupling to treat osteoporosis.

Excessive osteoclast activation disrupts bone homeostasis, contributing to osteoporosis (OP). While Runx2 is known to regulate osteoblast differentiation, its role in osteoclasts is less clear. Using conditional knockout models, we demonstrate that Runx2 directly drives osteoclast differentiation by regulating Ctsk transcription. However, its dual function in both osteoblasts and osteoclasts limits therapeutic potential. We identify Ip6k2 as a Runx2-interacting protein that enhances Runx2-dependent Ctsk transcription specifically in osteoclasts. Genetic deletion of Ip6k2 phenocopies Runx2 loss in osteoclasts, suppressing osteoclastogenesis and increasing bone mass without affecting osteoblast function. Notably, dual deletion of Runx2 and Ip6k2 yields no additive effects, indicating a shared regulatory pathway. Importantly, both genetic and pharmacological inhibition of Ip6k2 protect against estrogen deficiency- and age-induced bone loss. Collectively, our findings position Ip6k2 as a promising osteoclast-specific target and highlight that disruption of the Ip6k2-Runx2 complex may offer an effective strategy for OP treatment.